BACKGROUND: All known single gene defects in uric acid metabolism account for less than 5% of cases of significant hyperuricemia. But familial clustering of diseases within the group (gout, hyperuricemia, urolithiasis) occurs in at least 30% of cases and in some studies the number of first degree relatives manifesting the trait hyperuricemia reaches 50% of adult male relatives. Despite these findings, the larger studies of heritability of hyperuricemia were consistent with the hypothesis of multifactorial inheritance of this trait. It is unlikely that a biochemical abnormality which is so common in American males (4.8 - 7.4% of male subjects in the Framingham and Techumseh population studies) has a homogeneous etiology. Rather, as is becoming axiomatic for other common adult traits or diseases, the more common the condition, the greater the heterogeneity which must be accomodated by etiologic explanations. HYPOTHESIS: That the familial clustering of the biochemical abnormality hyperuricemia, while fitting a multifactorial model of heritability, will also fit a model of genetic heterogeneity. The latter will be a more useful model in guiding the search for a new major single gene mutations causing hyperuricemia. METHODS: Methods for resolving heterogeneity will be used in this study. First, a large population of affected probands will be identified (all patients with serum urate greater than 9.0 mg% by uricase method, and a random sample of those with serum urate between 7.0 - 9.0 mg) from a population of middle-aged males with a high incidence of hyperuricemia. Extensive pedigree studies are planned to examine serum urate and urinary uric acid excretion in all first degree relatives of such probands. Spouse controls will be obtained, and the study extended to second and third degree relatives in pedigrees with at least one first degree relative who is clearly hyperuricemic (greater than or equal to 99th percentile of controls). Pedigrees will be sorted into groups being careful to avoid introducing artificial bimodality. Probit analysis of each group, followed by maximum likelihood computer analysis will be used to seek segregation ratios indicating the presence of single gene effects. Additional studies will include twin studies with hyperuricemic index cases, linkage studies in large multigenerational pedigrees, and studies utilizing environmental provocation in pedigr (Text Truncated - Exceeds Capacity)